Abstract Research in my laboratory has made critical findings related to the molecular, cellular, and genetic basis of Myelodysplastic Syndromes (MDS), a complex and poorly understood hematopoietic stem cell (HSC) failure syndrome. The complexity and heterogeneity of MDS, and the lack of mouse models, remain as major obstacles to understanding and effectively treating this disease. A major focus of my lab has been the intersection of immune biology and MDS. Namely, we have uncovered and characterized genetically-driven aberrant activation of the Toll- like receptor (TLR) (i.e., innate immune) pathway in MDS HSC, and now have evidence that TLR signaling is a major unifying driver of MDS pathogenesis. While dissecting the role of TLR signaling in MDS HSC, we identified a critical function of TLR signaling in normal HSC, a finding that has broader implications in chronic immune-related disorders and hematopoietic processes. As such, my research program has developed transformative and innovative approaches to investigate the intersection of TLR signaling, hematopoiesis, and MDS, which serve as the foundation for this proposal: (i) to dissect the genetic, molecular, and cellular underpinnings of MDS, with an emphasis on genetically-driven activation of TLR signaling (Research Focus 1); (ii) to evaluate the developmental requirement of the TLR signaling hub, TRAF6, in normal HSC function and MDS (Research Focus 2); and, (iii) to use the knowledge gained by our basic research to identify and develop novel therapeutic modalities for the treatment of MDS (Research Focus 3). The proposed research will impact our understanding of the initiation, progression, and treatment of MDS.